1. Field of the Invention
The present invention is directed to a novel flavored extended release composition which forms a non-effervescent suspension when dropped into a liquid, and the methods of using said supplement, thereby improving swallowing through dispersing a large mass in a liquid and minimizing and eliminating gastric discomfort. This flavored extended release composition provides the additional benefits of palatable taste and pleasant appearance when dispersed into a liquid.
2. Description of the Related Art
Patients often encounter difficulty in complying with their drug regimen for various reasons. For example, dosage forms are often too large to comfortably swallow. In addition, many dosage forms taste unpalatable and even cause gastric discomfort. Further, patients have to take many doses throughout the day in order to maintain an effective blood level without taking toxic amounts.
An extended release dosage form remedies this problem because it can deliver the same amount of biologically active substance in one dose that an immediate release dosage form delivers in many doses. An extended release composition is one that achieves slow release of a biologically active substance over an extended period of time and extends the duration of action over that achieved by conventional delivery. An extended release drug delivery system provides several advantages over an immediate release drug delivery system of the same ingredient. These benefits include reduction of the frequency of administration and the maintenance of effective concentrations of the biologically active substance in the blood. The maintenance of an effective concentration in the blood reduces the chance of side effects and toxicity of the biologically active substance. This benefit is especially important when a toxic amount of a biologically active substance can cause illness and death.
Numerous approaches for administering extended and controlled release formulations have also been described in various references. For example, Busetti et al., U.S. Pat. No. 5,891,474, disclose a method of achieving a time specific delivery of a pharmaceutically active agent to a patient. The pharmaceutical agent is encased in a swellable polymeric coating, which delays the release of the pharmaceutical agent for a predetermined period of time depending on the thickness of the polymeric coating.
Baichwal et al., U.S. Pat. No. 5,662,933, disclose a extended release pharmaceutical formulation. The extended release formulation includes a gelling agent, an inert pharmaceutical diluent, a hydrophobic material and/or coating and a medicament for extended oral administration.
Goldie et al., U.S. Pat. No. 4,990,341, disclose a solid, controlled release oral dosage form. The dosage form comprises a therapeutic amount of hydromorphone or salt in a matrix for use with moderate to severe pain. The dosage is formulated such that the peak plasma level of hydromorphone is attained at 2-4 hours following administration of the dosage form.
Acharya, U.S. Pat. No. 5,686,094, discloses a controlled release formulation for the treatment of xerostomia. The delivery system comprises a polycarbophil coating surrounding an active agent. The coating system may also be used with cosmetics and household items where a controlled release effect is beneficial.
Yang et al., U.S. Pat. No. 5,576,022, disclose a controlled release tacrine drug delivery system comprising a sustained release composition and a controlled release composition wherein the controlled release composition is present at specific ratios to the immediate release composition.
Barry et al., U.S. Pat. No. 5,051,263, disclose a controlled release formulation comprising granules containing a carbomer and enough of an active substance to form a dose of the active substance. The granules are coated with an acrylic polymer. The solubility of the acrylic polymer controls the rate of dosage.
Sparks et al., U.S. Pat. No. 4,952,402, disclose a controlled release powder containing microparticles. The microparticles, which can contain an active pharmaceutical, have a predetermined dissolution rate which controls the rate of dosage. The powder is useful in foods and pharmaceuticals.
Staniforth et al., U.S. Pat. No. 5,858,412, disclose a sustained release formulation comprising augmented microcrystalline cellulose, and active ingredient and a sustained release carrier. The sustained release dosage form may be a tablet or a capsule containing excipients appropriate for sustained release technology.
Akiyama et al., U.S. Pat. No. 5,399,357, disclose a matrix prepared by dispersing a pharmaceutical active into a matrix comprised of either a fatty acid ester or a polyglycerol. The preparation has stable release controlling abilities, which contribute to the reduction of administration time of the active as well as a reduction of side effects.
Smith et al., U.S. Pat. No. 5,888,930, disclose a controlled release spray comprising a polymeric microporous bead containing an active ingredient. The bead has an anisotropic pore structure of large pores in the interior and small pores at the surface, with the graduation of pore size being continuous. The controlled diffusion of the active ingredient results in a controlled release product that reduces side effects and has a high stability.
Gergely et al., U.S. Pat. No. 5,587,179, disclose a pharmaceutical formulation in the form of an effervescent and/or disintegrating tablet. The biologically active substance, having an irritating taste, is coated by a matrix. This mixture may additionally contain a composition to compensate for electrolyte and salt loss in the body. Barry et al., U.S. Pat. No. 5,051,263, disclose a controlled release formulation comprising granules containing a carbomer and enough of an active substance to form a dose of the active substance. The granules are coated with an acrylic polymer. The solubility of the acrylic polymer controls the rate of dosage.
Sparks et al., U.S. Pat. No. 4,952,402, disclose a controlled release powder containing microparticles. The microparticles, which can contain an active pharmaceutical, have a predetermined dissolution rate which controls the rate of dosage. The powder is useful in foods and pharmaceuticals.
Staniforth et al., U.S. Pat. No. 5,858,412, disclose a sustained release formulation comprising augmented microcrystalline cellulose, an active ingredient and a sustained release carrier. The sustained release dosage form may be a tablet or a capsule containing excipients appropriate for sustained release technology.
Akiyama et al., U.S. Pat. No. 5,399,357, disclose a matrix prepared by dispersing a pharmaceutical active into a matrix comprised of either a fatty acid ester or a polyglycerol. The preparation has stable release controlling abilities, which contribute to the reduction of administration time of the active as well as a reduction of side effects.
Smith et al., U.S. Pat. No. 5,888,930, disclose a controlled release spray comprising a polymeric microporous bead containing an active ingredient. The bead has an anisotropic pore structure of large pores in the interior and small pores at the surface, with the graduation of pore size being continuous. The controlled diffusion of the active ingredient results in a controlled release product that reduces side effects and has a high stability.
Gergely et al., U.S. Pat. No. 5,587,179, disclose a pharmaceutical formulation in the form of an effervescent and/or disintegrating tablet. The active ingredient, having an irritating taste, is coated by a matrix. This mixture may additionally contain a composition to compensate for electrolyte and salt loss in the body.
Pxc3x6llinger et al, U.S. Pat. No. 5,695,784, disclose a flavor-masked pharmaceutical preparation. The preparation allows the administration of pharmaceutically active substances having a very unpleasant organoleptic taste, even in liquid form.
Cherukuri et al., U.S. Pat. No. 5,004,595, disclose a free-flowing particulate delivery system for providing enhanced flavor and sweetness to comestible compositions. The system comprises a powdered flavor composition encapsulated in a matrix comprised of a hydrophilic coating. The system is especially useful in pharmaceutical preparations as well as chewing gum.
Myers et al., U.S. Pat. No. 5,567,439, disclose a method and dosage unit form for delivery of a controlled release system. The controlled release system comprises instantaneous release components and delayed release components and is mixed with an uncured shearform matrix.
Ghebre-Sellassie et al., U.S. Pat. No. 5,084,287, disclose a pharmaceutical preparation comprising drug micropellets surrounded by a controlled release coating.
Yajima et al., U.S. Pat. No. 5,707,646, disclose the method of dissolving a drug in a polymer compound in a basic oxide containing sugar alcohol. This oral preparation is useful in masking the unpleasant taste of most drugs.
Raman et al., U.S. Pat. No. 4,983,404, disclose a flavor delivery system which offers a combination of extended and increased flavor intensity in chewing gum. The system is also useful in pharmaceuticals and food products as well as scratch-and-sniff packaging.
Regardless of the extended release properties of a dosage form, patients often find it difficult to comply with their drug regimen because the dosage form is large and difficult to swallow. This problem may be avoided by suspending the biologically active substance in a liquid that the patient can drink. However, patients may still have difficulty drinking the suspension if it is effervescent. Non-effervescent suspensions are easier to ingest, especially if the patient is nauseous.
Numerous approaches for administering an biologically active substance in an effervescent liquid suspension have been described in various references. For example, Hagemann et al., U.S. Pat. No. 5,211,957, disclose a solid, rapidly disintegrating effervescent tablet which produces an aqueous suspension when placed in liquid. The liquid dosage form contains diclofenac in micronised form provided with a swellable coating.
Grimmett et al., U.S. Pat. No. 5,670,170, disclose a pharmaceutical formulation comprising a medicament coupled with an effervescent component. The formulation may be suspended in water and imbibed. The preferred medicaments are antibiotics in combination with a citric acid-sodium bicarbonate couple.
Shimizu et al., U.S. Pat. No. 5,824,339, disclose an effervescent composition comprising a powder containing acid sensitive drugs that may be suspended in solution. The suspension provides a refreshing sensation upon ingestion.
Bonsen, U.S. Pat. No. 4,265,874, discloses a method for delivering a drug in a liquid. The drug provides an effervescent suspension in an environment that delivers the drug. The effervescence would cause the drug to have limited solubility under neutral and acid conditions.
In addition, approaches for administering a biologically active substance in a non-effervescent liquid suspension have also been described. For example, Recharge(trademark) Sports Drink, made by R. K. Knudson, Inc., is a fruit flavored drink designed for use during active sports to replace sodium and potassium lost during vigorous exercise. The drink contains 50 mg of potassium electrolyte. See R. K. Knudson advertisement.
The specific drug delivery system which is used to deliver a biologically active substance will have a great impact on the efficacy of that substance. For example, a variety of drug delivery systems have been utilized to effectively provide appropriate amounts of electrolytes. Electrolytes are essential to the body to regulate fluid balance. Electrolytes are salts that dissolve in water and dissociate. Cells cannot hold on to water molecules directly, but the polar nature of water causes it to aggregate around charged ions. See The Merck Manual, 135 (17th Ed. 1999). Cells sort out mineral ions so that some reside primarily outside the cell (for example, sodium and chloride) or primarily inside (for example, potassium and sulfate). During nerve transmission and muscle contraction, potassium and sodium change places across the cell membrane. The cell then quickly pumps them back into place. See Id. The relationship between intracellular and extracellular potassium concentrations strongly influences cell membrane polarization, which in turn influences important cell processes, such as the conduction of nerve impulses and muscle cell contraction. See Id. at 136.
The amount of various salts in the body must remain constant. If salts are lost, they must be replaced from an external source. Some situations, such as excessive vomiting, diarrhea, sweating, burns and the like may result in so much salt loss from that body that a medical emergency could result. See Id. 
The electrolyte potassium plays an essential role in maintaining fluid and electrolyte balance as well as cell integrity through its role in the sodium-potassium pump. Small alterations in plasma potassium concentrations can have major clinical manifestations. Therefore, the control of extracellular potassium concentration is a very high priority for the body. See Id. at 137.
Numerous factors affect the movement of potassium between the intracellular and extracellular fluid compartments. The most important factor is circulating insulin level. In the presence of insulin, potassium moves into cells. When circulating insulin is lacking, as with diabetes, potassium moves out of cells, raising the potassium plasma concentration. Stimulation of the sympathetic nervous system also affects transcellular movement. Beta-agonists promote the cellular uptake of potassium, while beta-blockers promote movement of potassium out of cells. Plasma pH also affects potassium concentrations. Acute metabolic acidosis promotes the movement of potassium out of cells. Changes in plasma HCO3 has the same effect. See Id. at 138.
There are several disorders of potassium metabolism, including hypokalemia, an abnormal movement of potassium into the cells, and hyperkalemia, an abnormal movement of potassium out of the cells. See Id. at 135-36 (17th Ed. 1999).
Because some potassium is found inside all living cells, most plants and animals can be a source of potassium. The best source for potassium is fresh fruits, vegetables and legumes. Accordingly, dietary deficiency of potassium is possible on a diet low on fruits and vegetables, although potassium deficiency occurs most commonly due to excessive losses of fluids. Conditions such as diabetic acidosis, dehydration, pica, villenous adenoma of the colon, prolonged vomiting or diarrhea can cause potassium deficiency. The regular use of certain drugs such a diuretics, steroids and laxatives also result in potassium deficiency. The first symptom of potassium deficiency is muscle weakness, followed by confusion and paralysis. See Id. at 137-38.
Potassium toxicity will not often result if the only source of potassium is food. However, toxicity may result from the overuse of potassium salt, especially in infants and the elderly. When the body receives too much potassium, the kidneys speed up the rate of excretion and eventually wear out. If the GI tract is bypassed, the excess potassium results in immediate death. If potassium is injected directly into a vein, the heart stops. See Id at 137.
Potassium chloride is the most common treatment for hypokalemia and hyperkalemia. However, potassium chloride is a known irritant to the gastrointestinal tract, and administration of the salt can cause nausea, vomiting, epigastric distress, abdominal discomfort and diarrhea. Excessive doses can cause weakness, listlessness, mental confusion, hypotension, vertigo, heart block and even death. Potassium chloride often shows signs of toxicity when administered to humans and should be administered carefully. See Id. at 139.
Various dosage forms of potassium chloride, such as uncoated and enteric-coated tablets and microcapsules have been used in the administration to humans, but frequently cause gastrointestinal ulcers, obstruction, hemorrhage and perforation as well as the symptoms of toxicity mentioned above. Various approaches for administering potassium have been described in published literature and various references. For example, Lippmann et al., U.S. Pat. No. 4,259,315, disclose pharmaceutical compositions for treating potassium deficiency in monogastric animals comprising controlled release gelatin capsules containing potassium salt and hydrophillic surfactant. The potassium chloride is contained in controlled release microcapsules and the surfactant reduces the likelihood of damage to mucosa.
Hsaio et al., U.S. Pat. No. 4,863,743, disclose a controlled release potassium chloride tablet comprising potassium chloride crystals coated with ethylcellulose and hydroxypropylcellulose. The coated crystals form micro pellets that can be crushed into tablets. These tablets disintegrate in an aqueous environment assuring a uniform dissolution of the active ingredient, which ensures a wide distribution of potassium over the gastric mucosa.
Mineral supplements containing potassium have also been described in various references. The Physician""s Desk Reference for Nonprescription Drugs describes various vitamin and mineral supplements which contain potassium. For example, One-A-Day(copyright) Maximum Multivitamin/Multimineral Supplement, made by Bayer Corporation, is a multivitamin and mineral supplement indicated as a dietary supplement to be administered once a day. The supplement contains 80 mg of potassium, 2% of the recommended daily allowance. See Physician""s Desk Reference for Nonprescription Drugs, 827 (20th Ed. 1999).
Macro-Mineral Complex, made by AdvoCare International, is a mineral supplement incorporating the full spectrum of bone-building nutrients in a bioavailable form to be taken two to six times a day. Each dosage contains 250 mg of potassium bicarbonate. See Physician""s Desk Reference for Nonprescription Drugs, 819 (20th Ed. 1999).
Vitasana(trademark) Daily Dietary Supplement, made by Pharmaton Natural Health Products, is a ginseng and multivitamin/mutimineral combination indicated as a dietary supplement for health and vitality, and is administered in gelcap form. This supplement should be taken twice a day and contains 16 mg of potassium chloride. See Physician""s Desk Reference for Nonprescription Drugs, 850 (20th Ed. 1999).
While electrolytes are vital to maintaining fluid balance and cell integrity, most sources of electrolytes present problems with patient compliance. For example, most compositions containing electrolytes are large and difficult to swallow. Alternatively, liquid dosage forms are easy to administer. Patients experiencing nausea and vomiting require electrolytes to replenish lost body fluids, however a patient experiencing nausea has great difficulty swallowing large tablets, as well as effervescent liquid suspensions. Alternatively, non-effervescent liquid suspensions are easy to administer. Furthermore, electrolyte supplements have an unpleasant taste that make the supplement ever more unpalatable, especially to children and the elderly. The above described compositions fail to fulfill the need for a non-effervescent tablet containing electrolytes which may be administered in liquid form.
In addition, the electrolyte potassium chloride is a known gastric irritant. Solid forms of potassium chloride lay along the stomach or intestinal lining and ulcerate the stomach or intestinal wall, leading to internal bleeding. Potassium chloride supplements that are not evenly dispersed and undiluted can cause great gastric discomfort and pain, if not injury.
Therefore, it would be desirable to provide a composition in an extended release form which overcomes the difficulties experienced in oral administration of large tablets and which would also have a palatable taste, while providing an appropriate dosage of an active which would be diluted and evenly dispersed before digestion. Such a supplement would be easier to administer, thereby increasing patient compliance. It would also be desirable to provide a drug delivery system which overcomes the side effects typically associated with the administration of certain substances, such as potassium, as well as to provide a solid dosage form of the above which would allow for ease of storage and transportation, and would not become suspended until the solid dosage form is placed in liquid. Accordingly, it would be desirable to provide a flavored and/or colored extended release composition which overcomes the deficiencies of the currently available compositions.
The present inventive subject matter provides a flavored extended release composition which forms a non-effervescent suspension when dropped into a liquid, and the methods of using said supplement. The present compositions overcome the deficiencies of current extended release compositions by minimizing and eliminating gastric discomfort, as well as providing the additional benefits of palatable taste and pleasant appearance.
One embodiment of the present inventive subject matter is a composition for oral administration to an animal, which comprises a plurality of extended release particles containing a biologically active substance, said particles being formulated in a solid dispersible tablet; a flavoring agent being formulated in the solid dispersible tablet; wherein the solid dispersible tablet forms a non-effervescent flavored and/or colored suspension when placed in a liquid; and wherein the non-effervescent flavored suspension after being orally administered to the animal releases the biologically active substance over a period of about 2 hours to about 48 hours.
A further embodiment of the present inventive subject matter is a composition for oral administration to an animal, which comprises a plurality of extended release particles containing a biologically active substance; a flavoring agent being formulated in the extended release particles; wherein the plurality of extended release particles forms a non-effervescent flavored suspension when placed in a liquid; and wherein the non-effervescent flavored suspension after being orally administered to the animal releases the biologically active substance over a period of about 2 hours to about 48 hours.
Another embodiment of the present inventive subject matter is a composition for oral administration to an animal, which comprises a plurality of extended release particles containing an alkaline salt of potassium, said particles being formulated in a solid dispersible tablet; a flavoring agent being formulated in the solid dispersible tablet; wherein the solid dispersible tablet forms a non-effervescent flavored and/or colored suspension when placed in a liquid; and wherein the non-effervescent flavored suspension after being orally administered to the animal releases the alkaline salt of potassium over a period of about 2 hours to about 48 hours.
Yet another embodiment of the present inventive subject matter is a method of improving patient compliance with a therapeutic or nutritional regimen, which comprises administering to an animal a non-effervescent flavored suspension formed by placing into a liquid a solid dispersible tablet comprising a flavoring and/or coloring agent and a plurality of particles containing a biologically active substance, said particles being coated with an extended release coating agent; wherein the non-effervescent flavored suspension after being orally administered to the animal releases the biologically active substance over a period of about 2 hours to about 48 hours.
An even further embodiment of the present inventive subject matter is a method of preparing an extended release composition for oral administration to an animal, which comprises coating a plurality of particles of a biologically active substance with an extended release coating agent to form extended release particles; blending the extended release particles, a flavoring agent and at least one excipient to form a compressible mixture; and compressing the compressible mixture into solid dispersible tablets which form a non-effervescent flavored and/or colored suspension when placed into a liquid.
The present inventive subject matter also included a method of preparing a potassium chloride composition for oral administration to an animal, which comprises coating a plurality of potassium chloride crystals with a coating agent to form extended release potassium chloride particles; and blending the extended release potassium chloride particles with a flavoring and/or coloring agent and at least one excipient to form extended release potassium chloride particles which form a non-effervescent flavored and/or colored suspension when placed into a liquid.